Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease for which there is no effective treatment. The only identified cause of ALS is mutations in the copper-zinc superoxide dismutase (SOD1) gene. Over 60 different mutations in SOD1 have been found to cause ALS and five of these have been shown to produce an ALS-like phenotype in transgenic mice. One of these mutations, murine G86R, is of particular interest because expression of the ALS phenotype is highly dependent upon the mouse genetic background. A genetic modifier locus from C57BI6/129Sv mice has been identified that prevents ALS onset in the mG86R SOD1 mice. This locus maps between D13mit36 and D13mit76 on mouse chromosome 13 with a maximum LOD score of 4.97. This same interval contains excellent candidate genes for the ALS-modifying locus; specifically, the spinal muscular atrophy (SMA)-associated genes Smn (survival motor neuron) and Naip (neuronal apoptosis inhibitory protein). The identification of genes that prevent the ALS phenotype in the mG86R SOD1 mice will provide insight into how mutations in SOD1 cause ALS. Furthermore, when the function of the genes that can prevent ALS is known, treatments may be developed. There are 3 major goals of this proposal: (1) to define a 1-2 Mb region where the genes that can prevent ALS onset are located; (2) to identify the specific genes and the genetic differences that can prevent ALS; and (3) to ascertain how these genetic differences can prevent ALS onset.